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Acylated derivative of homoharringtonine, preparation method therefor, and application thereof

a technology of acylated homoharringtonine and homoharringtonine derivative, which is applied in the field of natural medicine and pharmaceutical chemistry, can solve the problems of synthesis and application of novel mono-acylated and di-acylated homoharringtonine derivatives, and achieve the effect of improving the stability and stability of the homoharringtonine derivativ

Active Publication Date: 2016-08-30
INGERSOLL RAND IND U S INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The acylated derivatives demonstrate significantly improved anti-leukemia and anti-tumor activities, with enhanced inhibitory concentrations against leukemia cell lines and solid tumor cells, showing potential as more effective antitumor medicaments with reduced toxicity.

Problems solved by technology

Up to now, however, reports on the synthesis and application of novel mono-acylated and di-acylated homoharringtonine derivatives have not yet been seen.

Method used

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  • Acylated derivative of homoharringtonine, preparation method therefor, and application thereof
  • Acylated derivative of homoharringtonine, preparation method therefor, and application thereof
  • Acylated derivative of homoharringtonine, preparation method therefor, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Compound BS-HH-001

[0113]

wherein, HHT: homoharringtonine; Ac2O: acetic anhydride; DIPEA: N,N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DCM: dichloromethane; BS-HH-001: 2,6-diacetylhomoharringtonine; BS-HH-002: 6-acetylhomoharringtonine.

[0114]Homoharringtonine HHT (125 mg, 0.23 mmol), N,N-diisopropylethylamine (444 mg, 3.44 mmol) and 4-dimethylaminopyridine (28 mg, 0.023 mmol) are dissolved in dichloromethane (2 mL). Acetic anhydride (351 mg, 3.44 mmol) is added to the mixed solution and reacted for 24 h under 35° C. The reaction solution is rinsed with water and then with saturated sodium bicarbonate, dried and concentrated. The resulted crude product is purified via Preparative Liquid Chromatography to give compound BS-HH-001 (43.3 mg, 30%) as a white solid.

[0115]LC-MS: retention time: 1.11 min (98.7%), m / z: 630.5 [M+H]+.

[0116]1H NMR (300 MHz, CDCl3): δ 6.60 (d, 2H), 5.80-5.93 (m, 3H), 5.02 (s, 1H), 3.76 (d, J=9.9 Hz, 1H), 3.67 (s, 3H), 3.60 (s, 3H), 3.03-3....

example 2

Synthesis of Compound BS-HH-002

[0117]

wherein, HHT: homoharringtonine; Ac2O: acetic anhydride.

[0118]Homoharringtonine HHT (1 g, 1.84 mmol) is added to Ac2O (20 mL) and the reaction mixture is heated up to 80° C. and stirred for 13 h. After the reaction is completed, the reaction solution is concentrated to give a viscous crude product, to which diethyl ether is added for curing. Ethyl acetate is then added to the cured crude product to dissolve it. The mixture is rinsed with a saturated solution of potassium carbonate and then concentrated. The resulted crude product is purified by a Silica Gel Column Chromatography (EA:PE=1:2) to give a yellow oil, which is then recrystallized with diethyl ether to give compound BS-HH-002 (654 mg, 61%) as a white solid; the homoharringtonine HHT raw material is recovered in the meantime (354 mg).

[0119]BS-HH-002: LC-MS: retention time: 1.00 min (96.74%), m / z: 588.2 [M+H]+.

[0120]1H NMR (400 MHz, CDCl3): δ 6.62 (s, 1H), 6.55 (s, 1H), 5.99 (d, J=9.6 Hz,...

example 3

Synthesis of Compound BS-HH-077

[0122]

wherein, HHT: homoharringtonine; Yi: cyclopentylformic acid; 4-ppy: 4-(1′-tetrahydropyrrole)pyridine; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane.

[0123]Homoharringtonine (110 mg, 0.2 mmol), cyclopentylformic acid (46 mg, 0.4 mmol) and 4-(1′-tetrahydropyrrole)pyridine (60 mg, 0.4 mmol) are dissolved in dichloromethane (2 mL). Dicyclohexylcarbodiimide (83 mg, 0.4 mmol) is added to the solution, which is heated and refluxed for 3 h before filtration. The filtrate is concentrated, and the resulted crude product is purified with High Performance Liquid Chromatography to give BS-HH-077 (35.9 mg, 28%) as a light yellow powdery solid.

[0124]LC-MS: retention time: 1.52 min (95.63%), m / z: 642.6 [M+H]+.

[0125]1H NMR (300 MHz, CDCl3): δ 6.63 (s, 1H), 6.59 (s, 1H), 5.99 (d, J=9.0 Hz, 1H), 5.90 (m, 2H), 5.09 (s, 1H), 3.80 (m, 1H), 3.73 (s, 3H), 3.57 (s, 3H), 3.49-3.54 (m, 1H), 2.73-3.02 (m, 2H), 2.42-2.65 (m, 3H), 2.27 (m, 1H), 2.03-2.24 (m, 3H), 1.76-1....

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Abstract

The present invention belongs to the field of natural medicine and pharmaceutical chemistry, and relates to novel homoharringtonine acylated derivatives of formula (I) and formula (II) and a pharmaceutically acceptable salt thereof, to a process for the preparation of these compounds, compositions containing such compounds and their use in preparing antineoplastic medicaments.

Description

RELATED APPLICATIONS[0001]This application is a 35 U.S.C. §371 filing of International Application No. PCT / CN2012 / 080361, filed Aug. 20, 2012; which claims priority to International Patent Application No. PCT / CN2011 / 078589, filed Aug. 18, 2011. The entire contents of each are incorporated herein by reference.TECHNICAL FIELD[0002]The present invention belongs to the field of natural medicine and pharmaceutical chemistry, and relates to novel homoharringtonine derivatives, in particular acylated homoharringtonine derivatives, to a process for the preparation of these compounds, compositions containing such compounds and their use in preparing antineoplastic medicaments.BACKGROUND OF THE INVENTION[0003]Homoharringtonine (HHT), also known as O-3-[(2R)-2,6-dihydroxy-2-(2′-methoxy-2′-oxoethyl)-6-methylheptanoyl]cephalotaxine, is an alkaloid extracted and separated from Chinese herbal plants of Cephalotaxaceae family, in particular from cephatotaxus fortuneif or congeners thereof. Cephatot...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/55C07D491/147C07D491/20
CPCC07D491/20C07D491/147A61P1/04A61P1/16A61P1/18A61P11/00A61P13/08A61P15/00A61P17/00A61P19/00A61P25/00A61P27/16A61P35/00A61P35/02
Inventor XU, RONGZHENRONG, FRANKXIE, FUWENLAI, HONGXI
Owner INGERSOLL RAND IND U S INC
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